Systemic lupus erythematosis (SLE) is a systemic autoimmune disease with the potential to be directly involved in multiple organ systems. (See review by Kotzin, B. L., Cell 85:303-306, 1996.) The clinical manifestations of SLE include skin rash and joint pain, and severe and progressive kidney involvement. SLE patients typically present elevated serum levels of antibodies to nuclear constituents (i.e., antinuclear antibodies). In order to study the disease, workers have employed several animal models, including the F1 hybrid of New Zealand Black (NZB) and New Zealand White (NZW) mice, MRL mice homozygous for the lymphoproliferation (lpr) gene and BXSB mice, which carry the disease accelerating Yaa gene on the Y chromosome.
Principal targets of the autoantibodies produced in SLE patients include protein-nucleic acid complexes, such as chromatin, the U1 and Sm small nuclear ribonucleoprotein (snRNP) particles and the Ro/SSA and La/SSB RNP complexes (Tan, 1989; Cotson and Odell, 1995). Autoantibodies to phospholipids and cell surface molecules are also detected.
A majority of patients with SLE have symptoms of kidney failure. Clinical presentations typically include asymptomatic hematuria or proteinuria, acute nephritic or nephrotic syndromes, rapidly progressive glomerulonephritis and chronic renal insufficiency. (See Austin and Balow, Seminars in Nephrology 19(1):2-11, 1999.)
Current treatments have addressed lupus nephritis, although commonly used therapeutic regimes are potentially toxic and may be ineffective for some high risk patients. Typically, intensive immunosuppressive regimes are prescribed. For severe SLE, immunosuppressives such as chemotherapies and cyclosporin are used. Other treatments include treatment with corticosteroids and cytotoxic drugs. Alternative therapies include treatment with cyclophosphamide and prednisone. Side effects of long term use of prednisone include development of high blood pressure, diabetes and osteoporosis.
Currently, many pharmaceutical companies are searching for alternative therapies. La Jolla Pharmaceutical Company (La Jolla, Calif.) is conducting phase II/III trials of LJP394 Toleragen, designed to target B cells that display anti-double stranded DNA antibodies that are implicated in kidney damage. Genelabs Technologies, Inc. is conducting a phase III trial of DHEA, a naturally occurring androgen, with the goal of overall disease reduction. Other drug therapies include IDEC-131, a humanized monoclonal antibody that targets CD40 on helper T cells (Idec Pharmaceuticals Corp., San Diego, Calif.) and a 5G1.1 C5 complement inhibitor (Alexion Pharmaceuticals, New Haven, Conn.).
Lemire, et al., Autoimmunity 12(2):143-148, 1992, describes the attenuation by 1,25-dihydroxyvitamin D3 of some symptoms of experimental murine lupus in MRL/I mice.
1,25(OH)2D3 and Analogs
The 1xcex1-hydroxylated metabolites of vitamin Dxe2x80x94most importantly 1xcex1,25-dihydroxyvitamin D3 and 1xcex1,25-dihydroxyvitamin D2xe2x80x94are known as highly potent regulators of calcium homeostasis in animals and humans. More recently, their activity in cellular differentiation has also been established. As a consequence, many structural analogs of these metabolites, such as compounds with different side-chain structures, different hydroxylation patterns, or different stereochemistry, have been prepared and tested. Important examples of such analogs are 1xcex1-hydroxyvitamin D3, 1xcex1-hydroxyvitamin D2, various side-chain fluorinated derivatives of 1xcex1,25-dihydroxyvitamin D3, and side-chain homologated analogs. Several of these known compounds exhibit highly potent activity in vivo or in vitro, and possess advantageous activity profiles and thus are in use, or have been proposed for use, in the treatment of a variety of diseases such as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, multiple sclerosis, arthritis and certain malignancies.
1,25-Dihydroxyvitamin D3 as an Immunomodulator
The first indication that vitamin D might modulate immunity was the discovery that peripheral blood monocytes and activated T lymphocytes have 1,25-dihydroxyvitamin D3 receptors (reviewed in Manolagas, S. C., et al., Mol. and Cell. Endocrin. 43:113-122, 1985). Despite many investigations, 1,25-dihydroxyvitamin D3 immunomodulatory activity remains largely undefined and often controversial (reviewed in Manolagas, S. C., et al., supra, 1985; Rigby, W. F. C., Today 9:54-57, 1988; and Lemire, J. M., et al., J. Nutr. 125:1704S-1708S, 1995).
The action of 1,25-dihydroxyvitamin D3 on human peripheral blood mononuclear cells (PBMC) has been studied extensively in vitro. These in vitro experiments showed that the hormone inhibited mitogen-stimulated proliferation of the PBMC (Lemire, J. M., et al., J. Clin. Invest. 74:657-661, 1984; Rigby, W. F. C., et al., J. Clin. Invest. 74:1451-1455, 1984) by reducing IL-2 production (Lemire, J. M., et al., J. Immunol. 134:3032, 1985; Iho, S., et al., Immunol. Let. 11:331-336, 1985; Manolagas, S. C., et al., J. Clin. Endocrinol. Met. 63:394, 1986) at the level of gene transcription (Alroy, I., et al., Mol. Cell. Biol. 15:5789-5799, 1995). In contrast, Bhalla, et al. (Bhalla, A. K., et al., J. Immunol. 133:1748-54, 1984) reported that the hormone did not inhibit mitogen-stimulated mouse spleen and thymus cell proliferation, although it did inhibit antigen-stimulated proliferation of these cells. Lacey, et al. (Lacey, D. L., et al., J. Immunol. 138:1680-1686, 1987) reported that the hormone actually stimulated mitogen-induced proliferation of cloned mouse T-cells. No studies have directly addressed the action of the hormone on T lymphocyte differentiation and function in vivo.
Disparate results have been reported for T lymphocyte IFN-y synthesis in vitro. Rigby, et al. (Rigby, W. F. C., et al., J. Clin. Invest. 79:1659-1664, 1987) and Reichel, et al. (Reichel, H., et al., Proc. Natl. Acad. Sci. USA 84:3387-3389, 1987) showed that 1,25-dihydroxyvitamin D3 decreased IFN-xcex3 synthesis in mitogen-stimulated PBMC. However, Muller, et al. (Muller, K., et al., Immunol. Let. 35:177-182, 1993) reported that the hormone had no effect on IFN-xcex3 synthesis in human T-cell lines. The hormone inhibited cytotoxic T lymphocyte development but not cytotoxic function (Merino, F., et al., Cell. Immunol. 118:328-336, 1989).
There is controversy about 1,25-dihydroxyvitamin D3 action on monocyte/macrophage cells in vitro. 1,25-Dihydroxyvitamin D3 enhanced a myeloid leukemia cell""s differentiation to the macrophage phenotype (Manolagas, S. C., et al., supra, 1985). It also increased monocyte/macrophage production of M-CSF, TNF-xcex1, and prostaglandin E2, but decreased IL-12 synthesis (Lemire, J. M., et al., FASEB J. 8:A745 (abs), 1994). The hormone decreased macrophage costimulatory function for T-cell proliferation (Rigby, W. F. C. and M. G. Waugh, Arthritis Rheum. 35:110-119, 1992). Disparate results have been reported for 1,25-dihydroxyvitamin D3 effects on IL-1 synthesis in vitro. The hormone decreased IL-1 synthesis in some reports (Iho, S., et al., supra, 1985; Tsoukas, C. S., et al., J. Clin. Endocrinol. Metab. 69:127-133, 1989) and increased IL-1 synthesis in other reports (Amento, E. P., J. Clin. Invest. 73:731-739, 1987; Bhalla, A. K., et al., Immunol. 72:61-64, 1991; Fagan, D. L., et al., Mol. Endocrinol. 5:179-186, 1991). Likewise, some investigators reported that 1,25-dihydroxyvitamin D3 enhanced class II protein expression in vitro (Morel, P. A., et al., J. Immunol. 136:2181-2186, 1986) but others reported that it decreased class II protein expression (Amento, E. P., supra, 1987; Carrington, M. N., et al., J. Immunol. 140:4013-4018, 1988; Rigby, W. F. C., et al., Blood 76:189-197, 1990). Together these findings provide no clear and consistent view of how 1,25-dihydroxyvitamin D3 might modify macrophage function. No studies have directly addressed the action of the hormone on monocyte/macrophage differentiation and function in vivo.
There is also controversy about 1,25-dihydroxyvitamin D3 action on B lymphocytes (reviewed in Rigby, W. F. C., supra, 1988). Lemire, et al. (Lemire, J. M., et al., supra, 1984) reported that the hormone inhibited mitogen-stimulated IgG and IgM synthesis by human peripheral blood mononuclear cells. Suppressive and enhancing effects of 1,25-dihydroxyvitamin D3 on mitogen-stimulated B cell proliferation and on antibody synthesis in vitro have been shown. In vivo, 1,25-dihydroxyvitamin D3 has been reported to enhance antibody synthesis in some studies (Abe, J., et al., Endocrinology 124:2645-2647, 1989; Ross, T. K., et al., Vitamins Hormones 49:281-326, 1994; Daynes, R. A., et al., Infec. Immun. 64:1100-1109, 1996) and to inhibit it in other studies (Lemire, J. M., et al., supra, 1995).
The present invention is a method of preventing SLE symptoms in susceptible individuals and SLE patients by administering an amount of a vitamin D compound, preferably 1,25(OH)2D3 or analogs thereof, effective to prevent SLE symptom development or to diminish the SLE symptoms, respectively. (By xe2x80x9cSLE symptomsxe2x80x9d applicants refer to the lymph node swelling and proteinuria that are characteristic of SLE.) The method comprises selecting an SLE patient and administering a sufficient amount of the vitamin D analog to the patient such that the SLE symptoms are abated. Preferably, the patient will show a reduction in proteinurea levels to less than 100 mg/dL. Preferably, the patient will also be on a calcium-containing diet wherein the patient""s calcium intake is at least 800 mg/day/160 lb patient of calcium. A preferred range is 800 mg/day-1.5 g/day/160 lb patient.
In a particularly advantageous form of the reaction, the administered compound is either 1xcex1,25-dihydroxyvitamin D3 (1, 25-(OH)2D3), 19-nor-1,25-dihydroxyvitamin D2 (19-nor-1,25-(OH)2D3), 24-homo-22-dehydro-22E-1xcex1,25-dihydroxyvitamin D3 (24-homo-22-dehydro-22E-1,25-(OH)2D3), 1,25-dihydroxy-24(E)-dehydro-24-homo-vitamin D3 (1,25-(OH)2-24-homo D3), or 19-nor-1,25-dihydroxy-21-epi-vitamin D3 (19-nor-1,25-(OH)2-21-epi-D3). In a most preferred form of the invention, the compound is 1,25(OH)2D3.
A preferred dose of vitamin D compound for the present invention is the maximum that a patient can tolerate and not develop hypercalcemia.
If the vitamin D compound is not a la-hydroxy compound, a particularly advantageous daily dose of vitamin D compound is between 5.0 and 50 xcexcg per day per 160 pound patient. If the vitamin D compound is a 1xcex1-hydroxy compound, the preferred dose is between 0.5 and 25 xcexcg per day per 160 pound patient. In this embodiment of the invention, the amount of 1,25(OH)2D3 administered could be as high as 1.5 xcexcg per day per 160 pound patient. A preferred dose would be 0.5-5 xcexcg per day per 160 pound patient.
It is an advantage of the present invention that the method diminishes the SLE symptoms of proteinuria and lymph node swelling.
It is another advantage of the present invention that the method diminishes SLE symptom onset.
It is another advantage of the present invention that the method that the vitamin D compound is administered orally.
It is another advantage of the present invention that susceptible individuals can be prophylactically treated to prevent the development of SLE.
It is another advantage of the present invention that bone loss does not occur as a side effect of treatment.
Other advantages and features of the present invention will become apparent after examination of the specification, claims and drawings.